Adjusting for treatment switching in randomised controlled trials - A simulation study and a simplified two-stage method.

Estimates of the overall survival benefit of new cancer treatments are often confounded by treatment switching in randomised controlled trials (RCTs) - whereby patients randomised to the control group are permitted to switch onto the experimental treatment upon disease progression. In health technology assessment, estimates of the unconfounded overall survival benefit associated with the new treatment are needed. Several switching adjustment methods have been advocated in the literature, some of which have been used in health technology assessment. However, it is unclear which methods are likely to produce least bias in realistic RCT-based scenarios. We simulated RCTs in which switching, associated with patient prognosis, was permitted. Treatment effect size and time dependency, switching proportions and disease severity were varied across scenarios. We assessed the performance of alternative adjustment methods based upon bias, coverage and mean squared error, related to the estimation of true restricted mean survival in the absence of switching in the control group. We found that when the treatment effect was not time-dependent, rank preserving structural failure time models (RPSFTM) and iterative parameter estimation methods produced low levels of bias. However, in the presence of a time-dependent treatment effect, these methods produced higher levels of bias, similar to those produced by an inverse probability of censoring weights method. The inverse probability of censoring weights and structural nested models produced high levels of bias when switching proportions exceeded 85%. A simplified two-stage Weibull method produced low bias across all scenarios and provided the treatment switching mechanism is suitable, represents an appropriate adjustment method.

Cost-effectiveness of selective internal radiation therapy using yttrium-90 resin microspheres in treating patients with inoperable colorectal liver metastases in the UK.

OBJECTIVE: Selective internal radiation therapy (SIRT) using SIR-Spheres(®) (90)Y-labeled resin microspheres has been shown to be a well-tolerated, effective treatment in patients with inoperable liver-dominant chemotherapy-refractory metastatic colorectal cancer (mCRC). This study estimated the cost-effectiveness of (90)Y-resin microspheres compared to best supportive care (BSC) from a UK perspective. METHODS: Survival data from a comparative retrospective cohort study was analyzed and used in a state-transition cost-effectiveness model, using quality-adjusted life years (QALYs) gained as the measure of effectiveness. The model incorporated costs for the SIRT procedure, monitoring, further treatment, adverse events, and death. Utility values, reflecting patient quality-of-life, were taken from a published source. RESULTS: SIRT using (90)Y-resin microspheres compared to BSC improved overall survival by a mean of 1.12 life years and resulted in a cost per QALY gained of £28,216. In sensitivity analysis, this varied between £25,015-£28,817. CONCLUSION: In an area of large unmet need, treatment with (90)Y-resin microspheres offers a clinically effective and cost-effective treatment option.

The cost-effectiveness of celecoxib vs diclofenac in the treatment of osteoarthritis in the UK; an update to the NICE model using data from the CONDOR trial.

OBJECTIVES: The National Institute for Health and Clinical Excellence (NICE) health economic model for assessing the cost-effectiveness of celecoxib plus a proton pump inhibitor (PPI) compared to diclofenac plus PPI in the treatment of osteoarthritis has been updated using new adverse event (AE) risks from the CONDOR trial. In light of this new information, this study aimed to evaluate the incremental cost-effectiveness ratio (ICER) of celecoxib plus PPI compared to diclofenac plus PPI. METHODS: NICE developed a health economic model as part of their 2008 multiple technology assessment of treatments for osteoarthritis. The model was adapted for this study to update the relative risks of adverse events, using data from the CONDOR trial. RESULTS: Using the AE data from the CLASS trial alone, celecoxib plus PPI has an ICER of £9538 per QALY when compared to diclofenac plus PPI. When the AE data from CONDOR alone is used, this ICER decreases to £4773 per QALY. Using the pooled data from both trials, celecoxib plus PPI has an ICER of £9377 per QALY compared to diclofenac plus PPI. DISCUSSION: The results suggest that when new AE risks are used, celecoxib plus PPI remains a cost-effective treatment for OA when compared to diclofenac plus PPI. However, this analysis is limited by the short time horizon, and additional AEs that have not been considered.

The cost effectiveness of zoledronic acid 5 mg for the management of postmenopausal osteoporosis in women with prior fractures: evidence from Finland, Norway and the Netherlands.

OBJECTIVE: This study was conducted to assess the cost effectiveness of zoledronic acid 5 mg as a first-line treatment for the secondary prevention of fragility fractures in women with postmenopausal osteoporosis in Finland, Norway and the Netherlands. METHODS: A discrete-event, individual-patient computer-simulation model was used to compare the cost effectiveness of zoledronic acid with that of basic treatment (calcium and vitamin D) and commonly prescribed bisphosphonates in postmenopausal women aged 50-80 years who have experienced one previous fracture and have a bone mineral density T-score of -2.5. RESULTS: The cost per quality-adjusted life-year (QALY) gained with zoledronic acid compared with basic treatment ranged from being cost saving in all age groups in Norway, to costing approximately €19,000 in Finland and €22,300 in the Netherlands. Compared with the other branded bisphosphonates, zoledronic acid was cost saving in many scenarios, including all age groups in Finland. In Norway, zoledronic acid dominated branded risedronate and ibandronate in all age groups and dominated or had incremental cost-effectiveness ratios (ICERs) of up to NOK83,954 per QALY gained compared with branded alendronate. In the Netherlands, zoledronic acid dominated branded intravenous ibandronate in all age groups; compared with branded risedronate and oral ibandronate, zoledronic acid dominated or had ICERs of up to €4832 per QALY gained; compared with branded alendronate, it had ICERs of up to €48,383 per QALY gained. In all three countries, zoledronic acid may be cost effective compared with generic alendronate when patient compliance with drug therapy is taken into account. Sensitivity analyses showed that the model was robust to changes in key values. The main model limitations were the lack of real-life compliance and persistence data, and lack of country-specific data for some parameters. CONCLUSIONS: Using local or commonly used thresholds, this analysis suggests that zoledronic acid would be a cost-effective first-line option compared with other branded bisphosphonates and, in some scenarios, compared with generic alendronate, for the secondary prevention of fractures in women with postmenopausal osteoporosis in Finland, Norway and the Netherlands.

Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis.

Treatment options for secondary progressive multiple sclerosis (SPMS) are limited. Mitoxantrone is routinely used to stabilize disease progression; however, evolving evidence suggests clinical benefit from intensive treatment with autologous haematopoietic stem cell transplantation (HSCT). Given differences in cost and outcomes, preliminary cost-effectiveness studies are warranted if this approach is to be developed for more widespread application in SPMS. We developed a decision-analytic Markov model to explore the potential cost-effectiveness of autologous HSCT versus mitoxantrone in SPMS, using patient-level data from registry sources. The model evaluates the lifetime costs and health outcomes associated with disability progression and relapse. Sensitivity analyses were undertaken to examine the uncertainty surrounding cost-effectiveness outcomes. In the absence of randomised controlled trial (RCT) evidence, conditions for comparative analysis were not ideal. Under optimistic assumptions, HSCT is estimated to cost below pound3000 per quality adjusted life year gained. However, when a strict 6-month sustained progression rule is adopted, HSCT may be less effective and more expensive than mitoxantrone. The model results were sensitive to reducing procedural costs and HSCT-related mortality. We conclude that HSCT could potentially achieve an acceptable level of cost-effectiveness. However, caution should be exercised as large, high-quality RCTs comparing HSCT versus mitoxantrone are necessary to validate these findings.

Evaluation of surgical procedures for sex reassignment: a systematic review.

OBJECTIVES: To evaluate earlier reviews and literature concerning five individual surgical procedures for male-to-female (MTF) transsexism: clitoroplasty, labiaplasty, orchidectomy, penectomy and vaginoplasty. Further evaluations were made of eight surgical procedures for female-to-male (FTM) transsexism: hysterectomy, mastectomy, metoidoplasty, phalloplasty, salpingo-oophorectomy, scrotoplasty/placement of testicular prostheses, urethroplasty and vaginectomy. BACKGROUND: Increased prevalence and advances in surgical options available to patients requesting gender reassignment surgery have made this an important consideration for research. There remains a lack of systematic reviewing of the evidence, in particular, of the individual surgical options available. METHODS: Searches were undertaken in six electronic databases (Applied Social Sciences Index and Abstracts [ASSIA], Cochrane Library [Wiley Online], Embase [Ovid Online], Medline [Ovid Online], Medline in Process [Ovid Online], Psycinfo) providing coverage of the biomedical, grey literature and current research. RESULTS: Eighty-two published papers (38 MTF; 44 FTM) met the inclusion criteria identified across the 13 surgical procedures. For MTF transsexism there was no evidence satisfying the inclusion criteria concerning labiaplasty, penectomy or orchidectomy procedures. A large amount of evidence was available concerning vaginoplasty and clitoroplasty procedures. For FTM transsexism satisfactory outcomes were reported. Outcomes related to the ability to perform sexual intercourse, achieve orgasm and void whilst standing. Some complications were reported for both MTF and FTM procedures. CONCLUSIONS: The evidence concerning gender reassignment surgery in both MTF and FTM transsexism has several limitations in terms of: (a) lack of controlled studies, (b) evidence has not collected data prospectively, (c) high loss to follow up and (d) lack of validated assessment measures. Some satisfactory outcomes were reported, but the magnitude of benefit and harm for individual surgical procedures cannot be estimated accurately using the current available evidence.

Cost-utility analysis of deferasirox compared to standard therapy with desferrioxamine for patients requiring iron chelation therapy in the United Kingdom.

OBJECTIVE: The primary objective of the study was to evaluate the cost-utility of deferasirox (Exjade) compared to standard therapy using desferrioxamine (Desferal) for the control of iron overload in patients receiving frequent blood transfusions. The perspective adopted was that of the National Health Service in the UK. METHODS: Phase II/III clinical trials have shown deferasirox in the recommended doses of 20-30 mg/kg per day to have similar efficacy to desferrioxamine at equivalent doses in the control of chronic iron overload. The main difference between them is in the mode of administration. Desferrioxamine is administered parenterally as a slow subcutaneous infusion typically infused 8-12 hours a day for 5-7 days a week. In comparison, deferasirox provides 24 hour chelation via a once daily oral tablet dispersed in water or juice. An excel based economic model was developed to evaluate the annual healthcare costs and quality of life, or utility, benefits associated with differences in mode of administration, using beta-thalassaemia as the reference case. A community utility study using time trade-off methods was performed to determine utility outcomes associated with iron chelation therapy (ICT) mode of administration. RESULTS: In the reference case (patient mean weight 42 kg), deferasirox 'dominated' desferrioxamine, i.e. resulted in lower net costs and higher quality adjusted life years (QALYs). Drug dose and cost is patient weight related. Incremental cost per QALY gained was pound 7775 for patients with a mean weight of 62 kg. CONCLUSIONS: The cost-utility analysis did not take drug compliance into account. However, Deferasirox is cost-effective compared to standard iron chelation therapy with desferrioxamine, due to the cost and quality of life benefits derived from a simpler and more convenient oral mode of administration.

A cost-utility analysis of clopidogrel in patients with non-ST-segment-elevation acute coronary syndromes in the UK.

OBJECTIVE: To assess the long-term cost effectiveness of 1 year's treatment with clopidogrel on top of standard therapy (including aspirin; ASA) compared with standard therapy alone, in patients diagnosed with non-ST-segment-elevation acute coronary syndromes (ACS) in the UK. DESIGN: Cost utility analysis using a Markov model, incorporating clinical data from CURE (a multicentre randomised controlled trial, involving 12,562 patients) and data from UK observational studies. SETTING: Health economic evaluation carried out from the perspective of the UK NHS. PATIENTS: A representative cohort of 1000 UK patients aged 66 years, diagnosed with non-ST-segment-elevation ACS. INTERVENTIONS: Either a combination of 75 mg/day clopidogrel (300 mg loading dose, within 24 h prior to hospital admission) and standard therapy (including ASA, 75-325 mg/day) for 1 year followed by standard therapy alone for their remaining lifetime, or standard therapy alone (including ASA, 75-325 mg/day) for life. MAIN OUTCOME MEASURES: Incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: In the base case, the incremental cost effectiveness of the clopidogrel combination vs standard therapy alone is estimated as pounds 6991 per life-year gained and pounds 7365 per QALY gained. The probability that clopidogrel remains cost effective within the generally accepted pounds 30,000 per QALY threshold is more than 80%. The confidence interval around the relative risk for vascular death was identified as the main parameter affecting the estimated cost effectiveness. CONCLUSIONS: One year's treatment with clopidogrel is a cost effective intervention compared with standard therapy that should be considered as a routine treatment for patients with non-ST-segment-elevation ACS.

Effectiveness and cost-effectiveness of prognostic markers in prostate cancer.

This paper demonstrates how economic modelling can be used to derive estimates of the cost-effectiveness of prognostic markers in the management of clinically localised and moderately graded prostate cancer. The model uses a Markov process and is populated using published evidence and local data. The robustness of the results has been tested using sensitivity analysis. Three treatment policies of 'monitoring' (observation), radical prostatectomy, or a selection-based management policy using DNA-ploidy as an experimental marker, have been evaluated. Modelling indicates that a policy of managing these tumours utilising experimental markers has an estimated cost per quality-adjusted life year (QALY) of pound 12 068. Sensitivity analysis shows the results to be relatively sensitive to quality-of-life variables. If novel and experimental markers can achieve specificity in excess of 80%, then a policy of radical surgery for those identified as being at high risk and conservative treatment for the remainder would be both better for patients and cost-effective. The analysis suggests that a radical prostatectomy treatment policy for the moderately graded tumours (Gleason grades -7) modelled in this paper may be inferior to a conservative approach in the absence of reliable prognostic markers, being both more costly and yielding fewer QALYs.

[Modeling long-term results of basiliximab (SIMULECT) use in patients after kidney transplantation in Great Britain]. / Modelowanie dlugotrwalych skutków stosowania basiliximabu (SIMULECTU) u chorych po przeszczepieniu nerki w Wielkiej Brytanii.

Kidney graft survival prognosis could be performed in relation to the number of acute rejection episodes and their severity. The episodes of rejection could be modelled and based and the results obtained on this way could serve for prediction of a length of graft survival as well as for basiliximab treatment planning.

The implications of contact with the mentor for preregistration nursing and midwifery students.

AIM OF THE PAPER: To examine the extent to which preregistration nursing and midwifery students have contact with their named mentor, and the implications of this. BACKGROUND/RATIONALE: Mentorship has an important part to play in enabling preregistration nursing and midwifery students to gain the maximum benefit from clinical placements. Previous research has indicated that the benefits of mentorship to learners are related to the number of occasions on which the student and mentor work together. DESIGN/METHODS: A research project commissioned by the Sheffield and North Trent College of Nursing and Midwifery (now the University of Sheffield School of Nursing and Midwifery) provided an opportunity to examine the extent to which their named mentors were available to Project 2000 students, and the implications of this. Students and their named mentors were asked to keep an activity diary for 1 week. The main objective was to collect activity data to inform an analysis of the costs and benefits of clinical placements to service providers. This cost-benefit study has been published elsewhere. However, the data also cast light on the extent to which mentors were available to students, and the implications of this, and it is these findings which are presented here. RESULTS/FINDINGS: Students frequently worked shifts without their named mentors even though unrostered students often worked weekends, evening and night shifts in order to maximize time spent with their mentors. In the mentor's absence, other members of staff covered for some of their activities (in particular, direct and indirect supervision of students). However, students whose named mentors were absent spent significantly less time than other students working with a qualified member of staff as a partner in giving care. CONCLUSIONS: It is suggested that the extent to which named mentors are unavailable to Project 2000 students may be detrimental to the education and professional development of those students.

Treatment of irritable bowel syndrome: a review of randomised controlled trials.

Irritable bowel syndrome (IBS) is a common chronic disorder that is associated with significant disability and health care costs. The purpose of this paper is to review and assess published randomised controlled trials examining the clinical effectiveness of interventions for IBS for 1987-1998. A literature search was conducted to identify randomised controlled trials of IBS treatments: 45 studies were identified that described randomised controlled trials and of these, six fulfilled all three criteria used to assess the quality of randomised controlled trials, as described by Jadad and colleagues.(1) These criteria are: adequate description of randomisation, double blinding, and description of withdrawals and dropouts. It is concluded that there are few studies which offer convincing evidence of effectiveness in treating the IBS symptom complex. This review strongly suggests that future work should include well designed trials that: describe the randomisation method; use internationally approved diagnostic criteria; and are double blinded and placebo controlled. Clear well defined outcome measures are necessary. Inclusion of quality of life measures allows comparison between trials in different therapeutic areas. Conducting such studies will help to overcome some of the difficulties identified in this review.

Modelling in health economic evaluation. What is its place? What is its value?

This paper itemizes the current and developing roles of modelling in health economic evaluation and discusses its value in each role. We begin by noting the emptiness of the dichotomy that some commentators have sought to create between modelling and controlled trials as mechanisms for informing decisions. Both are necessary parts of the armoury. Recent literature discussions are examined and the accelerating prevalence of modelling is reported. The identified roles include: extrapolating outcomes to the longer term; adjusting for prognostic factors in trials; translating from intermediate to final outcomes; extending analysis to the relevant comparators; generalizing from specific trial populations to the full target group for an intervention and to other settings and countries; systematic sensitivity analyses; and the use of modelling for the design and prioritization of future trials. Roles are illustrated with 20 recent examples, mostly from within our own work analysing new or contentious interventions for the Trent Development and Evaluation Committee, which is planned to be incorporated into the UK National Institute for Clinical Excellence (NICE). Each role discussed has been essential at some point in this policy-making forum. Finally, the importance of quality assurance, critical review and validity testing is reiterated and there are some observations on processes to ensure probity and quality.

Should service providers be paid for providing pre-registration clinical placements?

The authors have argued elsewhere that second- and third-year student nurses and midwives on ward-based clinical placements make a service contribution which is of significant value to the service provider. The value of the service contribution made by students in community-based clinical placements is lower, not least because such placements cannot free staff time in the same way as on the wards, and thus the presence of students appears to form a cost to the service provider. It is clear that there is no case for introducing a system of payments for ward-based placements, but in community-based placements the position is less obvious. The argument hinges upon the perceived value to the service provider of the qualitative benefits associated with the presence of students on placement. Other studies have suggested that these benefits are such as to outweigh the associated costs. Because the presence of students on clinical placement is associated with both costs and benefits, efforts should be made to ensure that both ward-based and community-based placements are distributed as fairly as possible between locations so that no one location is unduly advantaged or disadvantaged by the number of students which it receives.

How effective are prevention strategies in reducing the prevalence of pressure ulcers?

The prevalence of pressure ulcers has remained constant at about 7% over the past 20 years, even though considerable time and money has been invested in various prevention strategies. This literature review explores whether pressure-prevention programmes can reduce the prevalence rate still lower or whether they are working but are limited by an increasingly aged population and rising patient acuity.